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Glyceroneogenesis has a new PEP in its step(s)
Alexandra E Jerrett1, Nicolai R Hathiramani2, Jessica B Spinelli3
1Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.
Cell
|May 14, 2026
Summary
Mitochondria export phosphoenolpyruvate (PEP) via SLC25A35. This finding reveals a new role for mitochondrial PEP in adipose tissue glyceroneogenesis and fatty liver disease development.
Area of Science:
- Cellular Metabolism
- Mitochondrial Biology
- Biochemistry
Background:
- Mitochondria are known to synthesize phosphoenolpyruvate (PEP).
- The mechanisms for PEP export from mitochondria and its physiological functions remained largely unknown.
- Understanding these processes is crucial for metabolic research.
Purpose of the Study:
- To identify the transporter responsible for mitochondrial phosphoenolpyruvate (PEP) export.
- To elucidate the physiological roles of mitochondrial PEP synthesis and export.
- To investigate the involvement of mitochondrial PEP in glyceroneogenesis and fatty liver disease.
Main Methods:
- Utilized genetic screening and biochemical assays to identify the PEP transporter.
- Employed cell-based models and animal studies to assess the function of the identified transporter.
- Analyzed metabolic pathways, including glyceroneogenesis, in various physiological and pathological conditions.
Main Results:
- Identified SLC25A35 as the specific transporter mediating phosphoenolpyruvate (PEP) export from mitochondria.
- Demonstrated that mitochondrial PEP synthesis is essential for glyceroneogenesis in adipose tissue.
- Uncovered a significant role for mitochondrial PEP in the development of fatty liver disease.
Conclusions:
- SLC25A35 is the key mitochondrial exporter of phosphoenolpyruvate (PEP).
- Mitochondrial PEP plays a critical, previously unrecognized role in adipose tissue metabolism and lipid accumulation.
- Targeting mitochondrial PEP export may offer therapeutic strategies for metabolic disorders like fatty liver disease.
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